The present invention relates to a breath test for the detection of a drug metabolite and, more particularly, to a breath test which can be used to analyze the rate of metabolism of a drug.
Drugs can be broadly defined to include any chemical agent which affects living processes. Generally, however, the term "drug" is used to refer to any chemical agent with therapeutic effects. By "therapeutic effects", it is meant that the chemical agent is useful in the prevention, diagnosis and/or treatment of disease. Hereinafter, unless otherwise stated, the term "drug" will be taken to be any chemical agent with therapeutic effects.
Increasing knowledge about human physiology and disease has brought an exponentially increasing number of new drugs onto the market. These new drugs provide more effective treatments for many diseases, such as cancer, AIDS and bacterial infections which are resistant to formerly effective medications. However, these new drugs themselves can cause mild to severe side effects and even idiopathic disease, which is a disease state caused by the drug itself. These undesirable and even dangerous reactions are directly related to the concentration of the drug in the body.
The concentration of the drug in the body, in turn, is regulated both by the amount of drug ingested by the subject over a given time period, or the dosing regimen, and the rate at which the drug is eliminated from the body. Hereinafter, the term "subject" refers to a human or lower animal to whom the drug is administered. The drug can be eliminated in two different ways, depending upon the molecular structure of the individual drug. First, the drug can be chemically modified into an inactive component or components which are then excreted. Second, the drug can be excreted from the body in a substantially unaltered form. Hereinafter, the term "elimination" of the drug is defined as the excretion or the chemical modification of the drug.
Chemical modification of the drug is a common pathway for elimination of the drug. Such modification most frequently occurs in the liver, although it can also take place in the blood, the kidney and other tissues. Modification can be classified as either synthetic or nonsynthetic [L. S. Goodman and A. Gilman, eds, The Pharmaceutical Basis of Therapeutics, The Macmillan Company, 1970, p.11]. Nonsynthetic modification involves such chemical reactions as oxidation or hydrolysis, often resulting in the cleavage of the drug molecule into two or more inactive molecules. Synthetic modification results in the formation of a chemical bond between the drug and an endogenous substrate such as a carbohydrate or amino acid. In either case, the modified drug can be referred to as a "metabolite" and the process of modification as "metabolism".
Identifying the type of metabolism which a particular drug will undergo in the body is further complicated by a number of factors. First, many drugs will be subject to a number of metabolic pathways within the body; that is, they will be able to undergo several different types of chemical modification. Second, although the choice of pathway or pathways is at least partly dependent upon the structure of the drug, predicting which pathway or pathways will be used is very difficult, and must usually be done through experimentation. Third, the particular metabolic pathway used will also depend upon the physiology of the individual subject. For example, a subject with hepatic dysfunction may eliminate a drug very differently from a subject with normal liver function. Fourth, the presence of other chemicals within the body can also change the metabolic pathway used by a particular drug. This can result in particularly dangerous side effects in those subjects taking multiple drugs simultaneously, or even in subjects ingesting non-therapeutic substances such as nicotine, since one drug can in effect overwhelm the capacity of a particular pathway, preventing other drugs from being properly modified. Of course, all of these factors also affect the rate at which at a particular drug is eliminated or "cleared" from the body. Thus, the particular type of chemical modification, and the rate at which this modification occurs, depends upon both the structure of the drug itself, and upon factors within the individual subject to whom the drug is administered.
When a new drug is undergoing clinical trials, both the rate at which the drug is eliminated from the subject and the type of metabolite(s) formed are determined. The rate of elimination will of course vary from subject to subject, so the drug must be tested in many individuals to produce an average elimination rate. Preferably, of course, many different groups of individuals will be tested, since children eliminate drugs more slowly than adults, for example, even when the dosage is given by body weight. The type of metabolite(s) formed must also be determined to indicate which pathway or pathways will be used. For example, if the drug is largely eliminated by the liver, a lower dosing regimen may be required for subjects with hepatic dysfunction. Thus, dosing regimens, or the rate and amount of drug which should be administered to a subject, can be determined from this information.
These dosing regimens have one major drawback, however: they are not tailored to the individual. At best, different regimens may be proposed for large groups of individuals, but even that is not always done. Thus, the geriatric patient with hepatic dysfunction, who is taking multiple drugs and who may have a low body weight, could potentially be given the same amount of a drug at the same rate as a young adult. Such a situation can be particularly dangerous for hospitalized patients, who frequently have both major organ dysfunctions and require multiple drug therapy.
"Therapeutic drug monitoring" is already used in order to adjust dosing regiments for individual patients in certain cases. In therapeutic drug monitoring, the concentration of a drug is measured in the blood of a patient, generally either just after the administration of a dose or just before the administration of the next dose [A. Goodman Gilman et al., eds, Goodman and Gilman's The Pharmacological Basis of Therapeutics, Pergamon Press, 1991, p. 30-31]. Usually, the concentration of a drug is measured just before the administration of the next dose, in order to determine the rate at which the drug is being cleared from the body. The concentration of the drug is measured just after the administration of a dose if the drug is almost completely eliminated between doses. Of course, if the concentration of the drug is measured more than once, the rate of clearance from the body can be more accurately determined.
Examples of drugs for which therapeutic drug monitoring is used include cyclosporine, which is an immunosuppressive agent [A. Lindholm and J. Sawe, Therapeutic Drug Monitoring, 17:570-3, 1995]. Indeed, A. Lindholm and J. Sawe specifically state that successful immunosuppression depends upon the tailoring of individual dosing regimens.
In these cases, it would clearly be highly useful to have a test which is simple, rapid, reliable and non-invasive and which could allow medical professionals to easily tailor the dosing regimen for the particular patient.
Unfortunately, currently available tests are invasive, difficult to administer or require an extended period of time for analysis. For example, therapeutic drug monitoring currently requires the analysis of a blood sample. Such a test is both invasive and complex, requires a laboratory to perform the analysis and requires an extended time period for analysis. Furthermore, such a test cannot be done in the home of a patient and, if performed in a doctor's office, often requires even more time for the sample to be sent away to a laboratory. Finally, such a test is difficult to perform many times on the same patient, due to the invasive nature of the sampling mechanism, and to the delay between the time the sample is obtained and the time it is analyzed.
Another possible method to determine the proper dosing regimen for an individual is to analyze the rate of metabolism of the drug in that individual by measuring the concentration of a metabolite. Metabolites can be detected when excreted in urine, for example. The concentration of these metabolites in at least one, and preferably in repeated samples would allow the rate of metabolism to be measured. However, although urine is relatively easy to collect, a laboratory is still required for analysis. Furthermore, such an analysis may require an extended period of time. Finally, the increased accuracy obtained with repeated samples makes many of these tests impractical. Unless the patient is in a hospital, collecting repeated samples and bringing them to the doctor's office or clinic is time-consuming and unlikely to result in patient compliance.
U.S. Pat. No. 5,100,779 to Watkins (hereinafter referred to as "Watkins") discloses a breath test in which a radiolabelled "reference drug", erythromycin, which is known to be metabolized by cytochrome p-450 is administered to a subject and the concentration of radiolabelled carbon dioxide in the exhaled breath of the patient is then measured in order to determine cytochrome p-450 activity. This activity is then correlated to the rate of metabolism of other drugs by using additional factors such as the age of the subject. However, such a test is necessarily restricted to those drugs whose metabolism can be directly correlated to the measured cytochrome p-450 activity on erythromycin. Furthermore, if multiple drugs are being administered to one patient, or even if the patient is ingesting non-therapeutic substances such as nicotine, the metabolic behavior of any one drug can be strongly affected, as noted above. In that case, the metabolism of a drug relative to the "reference drug" could be difficult to predict. It would be much more useful to have a breath test which can directly measure the rate of metabolism of each drug individually, rather than relying upon the predictive value of results obtained with a reference drug.
There is thus a widely recognized need for, and it would be highly advantageous to have, a test for the rate of drug metabolism which is easy, reliable, rapid, substantially non-invasive and sensitive, and which could more easily be used for multiple measurements.